Osteoporosis currently affects 10-12 million people in the United States. Although the majority are postmenopausal women, osteoporosis affects middle-aged men and also premenopausal women, the subject of this proposal. Although many young women with osteoporosis have an underlying secondary cause of bone loss, others have primary or idiopathic osteoporosis (lOP). The equivalent syndrome in men has been associated with low serum insulin-like growth factor 1 and osteoblast dysfunction. Although few data are available in premenopausal women, transiliac crest bone biopsies from a small number of affected women have revealed evidence of uncoupled remodeling, with increased bone resorption and markedly decreased formation. The central hypothesis of this proposal, therefore, is that lOP in premenopausal women is a disorder characterized by abnormal skeletal microarchitecture and remodeling, in which there is uncoupling of formation from resorption, with the imbalance favoring resorption. This hypothesis will be tested in a crosssectional, case-control study in which premenopausal women with lOP will be compared to normal women. Additional goals of this research proposal are to investigate the etiology and pathogenesis of lOP and to assess various measures of bone quality in women with this disorder. To accomplish these goals, we will characterize women with lOP in clinical, densitometric, and biochemical (gonadal and calciotropic hormones, bone turnover markers, bone resorbing cytokines) terms. Quantitative bone histomorphometry, microcomputed tomography (micro-CT), finite element analysis (micro-FE) will be applied to assess bone structure, remodeling, connectivity and strength. Fourier transform infrared spectroscopy (FTIRI) will be applied to evaluate the properties of bone mineral and matrix. We plan to pursue five specific aims in premenopausal women with lOP. 1. To describe the clinical phenotype. 2: To define the relationship between central and peripheral volumetric measurements of bone mineral density and fracture prevalence. 3: To define pathogenetic abnormalities in bone biopsy specimens utilizing quantitative histomorphometry, micro-CT, micro-FE and FTIRI. 4: to characterize estrogen status, and 5: to elucidate biochemical characteristics that may contribute to the pathogenesis of lOP. The results of these studies will have important therapeutic implications for the diagnosis and management of this disorder.